OTOL1

Summary

OTOL1 (otolin 1, HGNC:34071) is a protein-coding gene on chromosome 3q26.1, encoding Otolin-1 (A6NHN0). Collagen-like protein specifically expressed in the inner ear, which provides an organic scaffold for otoconia, a calcium carbonate structure in the saccule and utricle of the ear.

This gene encodes a secreted glycoprotein with a C-terminal complement Cq1-like globular domain that belongs to the C1q/tumor necrosis factor-related protein (CTRP) family. The encoded protein is expressed in the inner ear and forms a multimeric complex called the otoconia, together with cerebellin-1 and otoconin-90, as part of the otoconial membrane. It contains extensive posttranslational modifications including hydroxylated prolines and glycosylated lysines. Naturally occurring mutations in this gene are associated with abnormal otoconia formation and balance deficits resulting from vestibular dysfunction.

Source: NCBI Gene 131149 — RefSeq curated summary.

At a glance

• GWAS associations: 12
• Clinical variants (ClinVar): 68 total
• MANE Select transcript: NM_001080440

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:34071
Approved symbol	OTOL1
Name	otolin 1
Location	3q26.1
Locus type	gene with protein product
Status	Approved
Aliases	C1QTNF15, C1QTNF16
Ensembl gene	ENSG00000182447
Ensembl biotype	protein_coding
Entrez	131149

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000327928

RefSeq mRNA: 1 — MANE Select: NM_001080440 NM_001080440

CCDS: CCDS46948

Canonical transcript exons

ENST00000327928 — 4 exons

Exon	Start	End
ENSE00001292391	161499171	161499260
ENSE00001309982	161502307	161502369
ENSE00001327111	161496808	161497171
ENSE00001383325	161503026	161503942

Expression profiles

Bgee: expression breadth tissue_specific, 10 present calls, max score 44.62.

Top tissues by expression

125 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
prefrontal cortex	UBERON:0000451	44.62	gold quality
colonic epithelium	UBERON:0000397	41.51	gold quality
primary visual cortex	UBERON:0002436	39.56	gold quality
frontal cortex	UBERON:0001870	37.97	gold quality
Brodmann (1909) area 9	UBERON:0013540	36.97	silver quality
cortical plate	UBERON:0005343	36.47	gold quality
bone marrow cell	CL:0002092	36.16	gold quality
ganglionic eminence	UBERON:0004023	35.49	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	34.98	silver quality
cerebral cortex	UBERON:0000956	34.25	gold quality
skeletal muscle tissue	UBERON:0001134	33.38	gold quality
hindlimb stylopod muscle	UBERON:0004252	32.15	gold quality
bone marrow	UBERON:0002371	31.74	gold quality
muscle tissue	UBERON:0002385	31.06	gold quality
adrenal tissue	UBERON:0018303	30.94	gold quality
sural nerve	UBERON:0015488	30.93	gold quality
stromal cell of endometrium	CL:0002255	29.87	gold quality
liver	UBERON:0002107	29.35	gold quality
tonsil	UBERON:0002372	28.93	gold quality
duodenum	UBERON:0002114	28.14	gold quality
urinary bladder	UBERON:0001255	27.58	gold quality
lymph node	UBERON:0000029	27.57	gold quality
leukocyte	CL:0000738	27.11	gold quality
monocyte	CL:0000576	27.06	gold quality
temporal lobe	UBERON:0001871	26.96	gold quality
amygdala	UBERON:0001876	26.88	gold quality
brain	UBERON:0000955	26.47	gold quality
vermiform appendix	UBERON:0001154	26.42	gold quality
blood	UBERON:0000178	26.28	gold quality
gall bladder	UBERON:0002110	25.98	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.97

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 10)

• Identification and functional characterization of a similar protein in zebrafish. (PMID:15905077)
• calcium carbonate crystal growth data demonstrate that Otolin-1 and OC90 modulate in vitro calcite crystal morphology but neither protein is sufficient to produce the shape of otoconia (PMID:24748133)
• An expression and purification procedure for the C1q-like domain of human otolin-1 was developed. It forms stable trimers in solution in the presence of calcium ions. C1q-like domains were stabilized by the calcium ions. (PMID:29076638)
• Our results demonstrate a relationship between vitamin D and otolin-1 (PMID:29533337)
• Serum otolin-1 as a biomarker for benign paroxysmal positional vertigo: a case-control study. (PMID:34137365)
• Molecular mechanism of calcium induced trimerization of C1q-like domain of otolin-1 from human and zebrafish. (PMID:34140580)
• Natural Mutations Affect Structure and Function of gC1q Domain of Otolin-1. (PMID:34445792)
• N’-terminal- and Ca(2+)-induced stabilization of high-order oligomers of full-length Danio rerio and Homo sapiens otolin-1. (PMID:35447266)
• A potential serological biomarker for inner ear pathologies: OTOLIN-1. (PMID:36254652)
• Serum Otoconin-90 and Otolin-1 Concentrations in Benign Paroxysmal Positional Vertigo. (PMID:39456211)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	otol1a	ENSDARG00000001771
danio_rerio	otol1b	ENSDARG00000058960
mus_musculus	Otol1	ENSMUSG00000027788
rattus_norvegicus	Otol1	ENSRNOG00000021186

Paralogs (23): C1QTNF3 (ENSG00000082196), COL19A1 (ENSG00000082293), PDCD7 (ENSG00000090470), COL10A1 (ENSG00000123500), C1QL1 (ENSG00000131094), C1QTNF6 (ENSG00000133466), C1QL2 (ENSG00000144119), COL8A1 (ENSG00000144810), C1QTNF2 (ENSG00000145861), C1QC (ENSG00000159189), C1QTNF7 (ENSG00000163145), C1QL3 (ENSG00000165985), COL8A2 (ENSG00000171812), C1QTNF4 (ENSG00000172247), C1QB (ENSG00000173369), C1QA (ENSG00000173372), C1QTNF1 (ENSG00000173918), ADIPOQ (ENSG00000181092), C1QTNF8 (ENSG00000184471), C1QL4 (ENSG00000186897), C1QTNF9B (ENSG00000205863), C1QTNF5 (ENSG00000223953), C1QTNF9 (ENSG00000240654)

Protein

Protein identifiers

Otolin-1 — A6NHN0 (reviewed: A6NHN0)

All UniProt accessions (1): A6NHN0

UniProt curated annotations — full annotation on UniProt →

Function. Collagen-like protein specifically expressed in the inner ear, which provides an organic scaffold for otoconia, a calcium carbonate structure in the saccule and utricle of the ear. Acts as a scaffold for biomineralization: sequesters calcium and forms interconnecting fibrils between otoconia that are incorporated into the calcium crystal structure. Together with OC90, modulates calcite crystal morphology and growth kinetics.

Subunit / interactions. Homooligomer; disulfide-linked; probably forms homotrimers. Interacts with OC90. Interacts with CBLN1.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Domain organisation. The C1q domain mediates calcium-binding.

Similarity. Belongs to the OTOL1 family.

RefSeq proteins (1): NP_001073909* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001073	C1q_dom	Domain
IPR008160	Collagen	Repeat
IPR008983	Tumour_necrosis_fac-like_dom	Homologous_superfamily
IPR050392	Collagen/C1q_domain	Family

Pfam: PF00386, PF01391

UniProt features (29 total): modified residue 10, compositionally biased region 6, domain 4, glycosylation site 4, region of interest 2, signal peptide 1, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A6NHN0-F1	60.60	0.28

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (10): 133, 136, 163, 166, 169, 178, 223, 283, 301, 310

Glycosylation sites (4): 178, 202, 310, 381

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 15 (showing top): GOCC_COLLAGEN_TRIMER, chr3q26, GOBP_EAR_DEVELOPMENT, GOBP_PROTEIN_HOMOOLIGOMERIZATION, GOBP_SENSORY_ORGAN_DEVELOPMENT, GOBP_OTOLITH_DEVELOPMENT, GOBP_PROTEIN_COMPLEX_OLIGOMERIZATION, NABA_ECM_GLYCOPROTEINS, ZNF22_TARGET_GENES, GOBP_EXTERNAL_ENCAPSULATING_STRUCTURE_ORGANIZATION, GOBP_BIOMINERAL_TISSUE_DEVELOPMENT, GOBP_PROTEIN_CONTAINING_COMPLEX_ORGANIZATION, NABA_CORE_MATRISOME, NABA_MATRISOME, GOMF_CALCIUM_ION_BINDING

GO Biological Process (2): otolith mineralization (GO:0045299), protein homooligomerization (GO:0051260)

GO Molecular Function (3): calcium ion binding (GO:0005509), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (2): extracellular region (GO:0005576), collagen trimer (GO:0005581)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
biomineral tissue development	1
otolith development	1
protein complex oligomerization	1
metal ion binding	1
binding	1
cation binding	1
cellular anatomical structure	1
protein-containing complex	1

Protein interactions and networks

STRING

412 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
OTOL1	OC90	Q02509	819
OTOL1	OTOG	Q6ZRI0	704
OTOL1	TECTB	Q96PL2	682
OTOL1	TECTA	O75443	676
OTOL1	OTOGL	Q3ZCN5	656
OTOL1	OTOP1	Q7RTM1	622
OTOL1	TATDN3	Q17R31	605
OTOL1	BEND7	Q8N7W2	564
OTOL1	SLC26A5	P58743	541
OTOL1	ANGEL2	Q5VTE6	534
OTOL1	OR10A4	Q9H209	533
OTOL1	OR9A2	Q8NGT5	524
OTOL1	OR1D5	P58170	522
OTOL1	LYPD6B	Q8NI32	505
OTOL1	ST8SIA5	O15466	490
OTOL1	RPS6KC1	Q96S38	490

IntAct

2 interactions, top by confidence:

A	B	Type	Score
OTOL1	HNRNPM	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (4): OTOL1 (Affinity Capture-MS), HNRNPM (Proximity Label-MS), OTOL1 (Cross-Linking-MS (XL-MS)), RPL10A (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A0A060WQA3, A0MSJ1, A5PN28, A6NHN0, A8WGB1, A8WR59, B2RNN3, B7Z0K8, C7DZK3, O35167, O35348, O76368, O88207, P0C862, P12107, P13942, P20908, P20909, P23805, P25067, P25318, P25940, P42916, P83371, P98085, Q03637, Q07092, Q07563, Q0II24, Q0VF58, Q17RW2, Q30D77, Q32S24, Q3MI99, Q4ZJM7, Q4ZJN1, Q60467, Q61245, Q64739, Q6UXH8

Diamond homologs: A0A060WQA3, A5PN28, A6NHN0, B2RNN3, O75973, O88992, P02745, P02746, P08125, P0C862, P14106, P14282, P23206, P25067, P25318, P27658, P31720, P31721, P83371, P98085, P98086, Q00780, Q02105, Q03692, Q05306, Q05A80, Q06575, Q06576, Q06577, Q0II24, Q15848, Q2KIU3, Q2KIX7, Q3Y5Z3, Q4ZJM7, Q4ZJM9, Q4ZJN1, Q5E9E3, Q5FVH0, Q5RJ80

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

68 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	63
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

624 predictions. Top by Δscore:

Variant	Effect	Δscore
3:161499165:TTCTA:T	acceptor_loss	0.9900
3:161499168:TAGGT:T	acceptor_loss	0.9900
3:161499170:G:GC	acceptor_loss	0.9900
3:161499257:AAAG:A	donor_loss	0.9900
3:161499258:AAGG:A	donor_loss	0.9900
3:161499259:AGG:A	donor_loss	0.9900
3:161499261:G:C	donor_loss	0.9900
3:161499262:T:G	donor_loss	0.9900
3:161499164:T:G	acceptor_gain	0.9800
3:161502301:TCTTA:T	acceptor_loss	0.9800
3:161502302:CTTAG:C	acceptor_loss	0.9800
3:161502303:TTA:T	acceptor_loss	0.9800
3:161502304:TA:T	acceptor_loss	0.9800
3:161502305:A:AG	acceptor_gain	0.9800
3:161502305:A:C	acceptor_loss	0.9800
3:161502306:G:GG	acceptor_gain	0.9800
3:161499169:A:AG	acceptor_gain	0.9700
3:161499170:G:GG	acceptor_gain	0.9700
3:161497167:GCCAG:G	donor_gain	0.9600
3:161497168:CCAGG:C	donor_loss	0.9600
3:161497169:CAGGT:C	donor_loss	0.9600
3:161497170:AG:A	donor_loss	0.9600
3:161497171:GGT:G	donor_loss	0.9600
3:161497172:G:T	donor_loss	0.9600
3:161497173:T:G	donor_loss	0.9600
3:161503020:TTTCA:T	acceptor_loss	0.9600
3:161503021:TTCAG:T	acceptor_loss	0.9600
3:161503022:TCAGG:T	acceptor_loss	0.9600
3:161503023:CA:C	acceptor_loss	0.9600
3:161503024:A:C	acceptor_loss	0.9600

AlphaMissense

3084 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:161503886:A:C	S460R	0.990
3:161503888:C:A	S460R	0.990
3:161503888:C:G	S460R	0.990
3:161503677:T:C	F390S	0.988
3:161503647:T:C	F380S	0.985
3:161503830:T:A	V441D	0.985
3:161503541:T:C	F345L	0.983
3:161503543:C:A	F345L	0.983
3:161503543:C:G	F345L	0.983
3:161503898:G:T	G464W	0.982
3:161503893:T:C	F462S	0.981
3:161503542:T:C	F345S	0.979
3:161503836:T:C	L443P	0.979
3:161503544:A:C	S346R	0.978
3:161503546:C:A	S346R	0.978
3:161503546:C:G	S346R	0.978
3:161503654:C:G	C382W	0.976
3:161503670:T:G	Y388D	0.976
3:161503836:T:A	L443H	0.976
3:161503899:G:A	G464E	0.974
3:161503664:G:T	G386W	0.973
3:161503898:G:A	G464R	0.972
3:161503898:G:C	G464R	0.972
3:161503646:T:C	F380L	0.968
3:161503648:T:A	F380L	0.968
3:161503648:T:G	F380L	0.968
3:161503641:G:T	G378V	0.967
3:161503542:T:G	F345C	0.965
3:161503592:T:C	F362L	0.964
3:161503594:T:A	F362L	0.964

dbSNP variants (sampled 300 via entrez): RS1000032899 (3:161495733 C>T), RS1000059774 (3:161495496 C>T), RS1000836708 (3:161500013 G>A), RS1000907687 (3:161501445 T>A), RS1001283096 (3:161498153 T>C), RS1001293206 (3:161503993 C>G,T), RS1001438337 (3:161497977 T>C), RS1001515234 (3:161498380 G>A), RS1001580853 (3:161504404 T>A), RS1001786716 (3:161500315 T>A), RS1002293919 (3:161499605 G>C,T), RS1002846661 (3:161502787 A>G), RS1002960029 (3:161497131 A>C,G), RS1003371976 (3:161502504 T>C), RS1004462814 (3:161502145 G>A)

Disease associations

OMIM: gene `` | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST001167_3	Aging (time to death)	1.000000e-06
GCST003944_22	Hepcidin/ferritin ratio	3.000000e-06
GCST004946_117	Schizophrenia	8.000000e-10
GCST006484_17	Type 2 diabetes	5.000000e-07
GCST006484_19	Type 2 diabetes	8.000000e-07
GCST007201_148	Schizophrenia	3.000000e-08
GCST007201_388	Schizophrenia	1.000000e-07
GCST007324_37	Adventurousness	3.000000e-08
GCST007328_77	Alcohol consumption (drinks per week)	8.000000e-09
GCST009441_18	Age-related cognitive decline (memory) (slope of z-scores)	2.000000e-06
GCST012310_20	Schizophrenia x sex interaction	8.000000e-06
GCST012311_1	Schizophrenia x sex interaction	9.000000e-06

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0022597	aging
EFO:0007901	hepcidin:ferritin ratio
EFO:0008579	risk-taking behaviour
EFO:0007710	cognitive decline measurement
EFO:0008343	sex interaction measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

7 total (human), top 7 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
theaflavin-3,3’-digallate	affects expression	1
Resveratrol	affects cotreatment, decreases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Endosulfan	decreases expression	1
Plant Extracts	decreases expression, affects cotreatment	1
Triclosan	increases expression	1
Valproic Acid	decreases methylation	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.